In this Founder Stories interview, Joshua Elkington of Piper Jaffray talks with Kenneth (Ken) Mills, President and CEO of Regenxbio, about the company’s AAV gene‑therapy platform and its strategic direction. Regenxbio leverages novel adeno‑associated virus (AAV) capsid sequences discovered in Dr. Jim Wilson’s laboratory, which provide higher transduction efficiency and expression. The company runs a dual model: licensing the technology to external partners (about 8 licensees with 23 programs) while building its own vertical pipeline focused on metabolic diseases, central nervous system (CNS) disorders, and ophthalmology. Mills reflects on the field’s evolution since the early 2000s, citing key translational milestones such as the RPE65 and hemophilia B AAV2/AAV8 successes that shaped confidence in the platform. He highlights ongoing challenges—vector manufacturing, promoter and codon optimization, and the need for thoughtful indication selection. The interview delves into Regenxbio’s lead programs: a homozygous familial hypercholesterolemia (HoFH) gene‑therapy using AAV8, which has entered IND‑enrollment with a dose‑escalation plan targeting up to 12 patients; MPS I/II programs that aim to deliver enzyme replacement across the blood‑brain barrier by transducing CNS cells; and an ophthalmology program for wet age‑related macular degeneration. Mills discusses clinical development considerations, including the one‑time‑treatment paradigm, determination of minimally effective dose, safety margins, and regulatory expectations. Overall, the conversation paints a picture of a company leveraging cutting‑edge AAV technology, learning from past translational experiences, and applying those lessons to build a focused, clinically‑driven pipeline.
Chapters
Okay, we're going to get started with our next session. Joshua Elkington from the Piper Jaffray biotech team back again with Ken Mills, President and Chief Executive Officer of Regenexx Bio. Ken, give us a snapshot of Regenexx Bio and what differentiates your, your AAV platform.
Yeah, thanks, Josh. Good to see you. Thanks, everyone. So Regenexx Bio is an AAV gene therapy company. So we're focused on using the adeno-associated virus, and in vivo gene delivery methods to correct a variety of diseases across multiple therapeutic areas. The differentiator for Regenexx Bio is that when we formed the company, we gained access to novel sequences of AAVs that were discovered in the lab of Dr. Jim Wilson at the University of Pennsylvania that showed improvements to previously existing naturally occurring AAVs. Derivatized that technology into a bimodal form of the business. We have both started licensing the technology for applications outside of Regenexx's core areas of focus. And we have, I think at last count, 8 external licensees developing about 23 programs between preclinical and early clinical stage. And then in 2014, 2015, Regenexx transitioned into building out vertical infrastructure to develop its own programs. And we're now focused in metabolic diseases, CNS diseases, and diseases in ophthalmology.
So Regenexx Bio is really, to your point, at the center of a whole world of preclinical and clinical gene therapy programs. As you watch them translate from the preclinical to the clinical setting, what to you are the key lessons? How is it informing your own choice of internal pipeline candidates, and where, if any, are there gaps in translating from a non-human primate or other animal into the human setting?
That's a broad spectrum question.
You've got 13 minutes to answer, and then I'll be done.
Yeah. You know, since getting into this space myself in 2007 and then forming the company, in 2009 with Jim, who had a much more retrospective perspective on the history and development of gene therapy in general. I think that the early to mid-2000s were sort of a pivot point for the field, in particular of AAV gene therapy, where there had been a fair amount of translational work that was being done, but maybe some technology limitations with vectors, maybe manufacturing and other things that were maturing. But really there hadn't been enough successes yet, I think, to begin to start to measure exactly where to move next. And I think there are some things that started to occur internal and external to Regenexx that were really meaningful to our thinking at the time when we formed the company. Certainly the demonstration of RPE65 using the AAV2 vector was something that was really meaningful. It followed a few years later with the demonstration in treatment of hemophilia B with the AAV8 vector, which was with one of the vectors that Jim discovered. And I think there's actually been a host of several important additional milestones, both translationally and in the clinic, that have continued to show us for AAV gene therapy where it works well, what the technology is actually best suited for. And I think sometimes with new technologies, when you, when you don't know and there are a lot of unknowns, and it can be exciting and innovating to embrace a new technology, You think it can do a lot more perhaps than it can. I think what I'm proud to say today about Regenexx, and I think about the field of AAV gene therapy in general, is that I think the companies, the scientists, the business leaders, the clinicians are starting to be much more thoughtful about the application of AAV gene therapy. And it's starting to bear fruit. I think more and more clinical studies now, more and more preclinical translational work are mapping onto clinical successes. And I think in a meaningful way, that's going to continue.
So we'd spent a whole panel talking about optimizing either the vectors, the promoters, the delivery. Where do you see the biggest gains to be had as you think about the nav vectors and the ability to further hone them in for various disease indications?
Yeah, so, you know, I think that one of the things that was exciting to me when I first got a look at some of the data that Jim and colleagues and frankly other investigators had generated with the novel sequences, what I thought that there had been a major advancement in the ability for AAV gene therapy vectors to express at much higher levels. And that seemed like it was going to break through a ceiling that existed previously and perhaps access more diseases legitimately with therapeutic effect. That clearly was a major advancement and it came out of an academic institution. And I think that while that advancement was significant, there were other things about the field of gene therapy and AAV gene therapy that still needed investment and improvement. And one of those areas, Josh, you and I have discussed is manufacturing. You know, I think that that is another area certainly where we as Regenexx, and I know other of our licensees and, you know, other peers in the industry have continued to invest a lot in drawing improvements so that not just from an industrial scale perspective, but also even in advancing first-in-human studies, we have better product that we're putting into people that's more efficient than it was in the earlier days of gene therapy in general. And of course, that's a natural evolution. So I think From where I sit, you know, the advancement of the novel vectors has been a significant advancement for the field in terms of achieving higher levels of expression and efficiency and achieving more therapeutic window effect. Manufacturing advancements are really helping. And then I think there are other areas just where biotech has evolved overall, looking at borrowing from other fields, other fields in biotech, looking at the use of new promoters, looking at things like codon optimization of genes to get better transcription and translation. These are all things that are not necessarily in the wheelhouse of the AAV development investigator, but they can borrow from areas where other people are developing and enhancing, and we've begun to.
So going back to your point about increasing thoughtfulness about applications, what you've learned that works well or doesn't work as well, maybe a little bit more tangibly, what are you seeing that's working well that's now informed your programs for HOFH, MPS I and II, and also in the ophthalmology setting for wet AMD.
Yeah, so, um, great. The, uh, the lead program that Regenexx has is for a disease called homozygous familial hypochondrolemia, and this is a disease where you inherit two genes that are defective for a specific receptor that's available normally in most of us to help clear cholesterol. And when you don't have appropriate function in, in this receptor, then you get very high levels of cholesterol. And we all know canonically that that can lead to bad outcomes. But when it's severely high, it can of course lead to the worst outcomes. What we thought about in early in the development of this program— it was actually our scientific founder and another collaborator of his at the University of Pennsylvania— was that there was one vector in particular, AAV8, that had a great property of transducing hepatocytes, or liver cells, which is where this receptor happens to naturally occur most prevalently, and that we could get very high levels of expression. First, they showed it with kind of reporter genes. It was more like a, you know, lab experiment. And they said, boy, if we can get a lot of hepatocytes lighting up with this reporter, what if we could put in the gene for the LDL receptor, which is this receptor, and and repopulate its function and activity in the liver. And they had a really good thought about that. The program sort of, I would say, puttered along for many years on grant funding and other things. I think the theory was right. And then here's something that really informed our decision, you know, internal to Regenexx about the meaningfulness of this program. Another group in another academic center ran a study and published results in the New England Journal of Medicine using the same vector, AAV8, to transduce the liver to express a blood clotting factor. And, you know, several people may know about this New England Journal publication that came out in late 2011. Well, as soon as we all saw that, you know, then the light bulb went off. Wow, AAV8 really is— it's really getting phenomenal transduction, albeit in a different disease. We really need to put our foot on the pedal of a homozygous FH development program. And we've worked for several years to do that. And now I'm happy to say, at least within Regenexx, it's the first active IND that we have had as a company.
So you're at the enrollment stage. Maybe you can discuss some of the, how facile it is to enroll patients into a gene therapy company for the indication and maybe take us through some milestones for development. Are you looking to dose escalate? What's the cadence of the program likely to be?
Yeah, so with respect to HOFH and I think gene therapy programs in particular, you know, generally the model is, especially in the orphan populations of which HOFH is designated in the US and worldwide as an orphan indication, that we're trying to focus on a small population. And, you know, what we realize with gene therapy is that The concept of the product is a one-time treatment, a one-time administration that's going to durably deliver therapeutic effect. And that would be a phenomenal outcome for approved products in our space. The one trade-off with the approach of gene therapy to get to that point is that you can only administer the product one time. And what that means is if you miss on the first administration and you don't get that therapeutic effect, you can never administer that same product again, in all likelihood from what we know today, to that patient. So it means when we account for the kind of ethical considerations and the scientific considerations, many of us in the space, especially in these orphan indications, try to establish in the animal models before we even dose a patient what we call the minimally effective dose. And so that's exactly what we have done in the homozygous FH clinical study that we're running. And what we've been able to do is borrow from some of the clinical data like what we've seen in this hemophilia study that's similar, but slightly different. And then also our own animal modeling to hopefully come in so that the first patient, although we're doing a safety study according to FDA standards, might see some minimally effective dose response and therapeutic effect. And then, so that's going to be our first dose, Josh, and then we will dose up from there to try and show increased effect and what that means linearly over the course of enrollment of a relatively small study for HOFH, which we're targeting up to 12 patients. We might like to come in at a certain percentage of reduction, let's say in serum cholesterol in these patients, and then by the second dose, and if needed a third dose, see much more dramatic reduction. And so that will occur for us with the IND open. We're looking to enroll patients over the next couple of months and be in a position to report the outcome of this in 2017.
And what's clinically meaningful and relevant, and how far are you able to push in your mind on the dose before you start, I guess, running into theoretical safety concerns?
Yeah, so I think our perspective is that the nice thing about the AAV platform is that the theoretical dose-limiting toxicities associated with the AAV itself are at a time theoretically, and I think now proven to be at a pretty high level. We have seen some of our licensees administer AAVs, I would say, at doses that are a log or two greater than what we are getting set to do in our HO-FH study, which means we potentially have the ceiling to go much, much higher than where we're going to start. But we already think we're starting at something that might be minimally effective. So, you know, we're sort of walking that balance with the regulators and our own scientists and clinicians. I think that, you know, what we hope and expect to see is we've looked at this disease for a number of years through many different lenses. Frankly, since we started the program in the lab, products have been approved for this disease, not addressing the underlying cause, I think, like we are with gene therapy, but addressing compensatory pathways to help reduce cholesterol in these patients. And we've seen things that have succeeded and failed for patients and also translating that into the market. We know that products right now can reduce cholesterol in some of these patients with side effects at 25 to 40% levels. It's not insignificant. We consider that, you know, a pretty low bar for patients that have LDL-C resting at 500 to 1,000. We want to drive that down further. So, you know, a target product profile for us is to do that with gene therapy get at least that much reduction and have it be durable in a one-time administration and maybe erase some of the safety profile concerns that other products have.
You took us through the rationale for the HOFH program. What's the background rationale that gives you confidence in MPS1 or MPS2?
Yeah, so MPS1 was a little different. It was all really based on observational animal data. There, so in MPS1, quickly, we took an approach where there was an approved product on the market that's sold by BioMarin and Genzyme. That treatment administration treats the peripheral manifestations of a disease in kids and adults who also have a CNS component. In the case of the CNS component, the enzyme replacement therapy doesn't cross the blood-brain barrier, so even though people are getting systemic benefit, they're not getting CNS. We hypothesize that with a gene therapy, if we could transduce the brain cells, more cells in the CNS, we could perhaps correct that aspect of the disease, but we're using the same gene encoding the same enzyme that enzyme replacement therapy is using. So we did the animal experiments and we've published the data, and I think in the large animal models, cats and dogs, it's been a phenomenal response, and we're really excited to bring that into human studies because it's a really significant unmet need. It's a little bit of a different approach.
Yeah, well, more and more programs going into the clinic for, for you and your partners each year. It's, it's more clinical data reading out, so looking forward to some additional updates. I think we're, uh, we're a little bit post time, so we're going to let the next company get started. Ken, thank you so much.
